Malaria caused by P. falciparum continues to be a global problem with devastating consequences. A greater understanding of the immunologic and parasitologic factors associated with infection and disease is badly needed, and will accelerate the development of highly protective vaccines for both mothers and children. Pregnancy malaria is associated with low birth weight, maternal anemia, and gestational hypertension, and both inflammation and the fetal response to infection may contribute to these poor outcomes. Childhood malaria is a major cause of mortality, and we have found that risk of childhood malaria is related to in utero exposure to pregnancy malaria, as well as other host factors like iron status and constitutive cytokine levels. Pregnancy malaria is caused by a distinct parasite binding phenotype, and as our primary hypothesis in this study we speculate that severe childhood malaria parasites may also have distinct features. A longitudinal cohort study is being conducted in Ouelessebougou, Mali, an area of intense seasonal transmission. 2000 pregnant women and their infants and several hundred children ages 0-3 years have been enrolled; all pregnant owmen have now completed their pregnancies, and the children followed up to age 5 years, with clinical evaluation and periodic venous and peripheral blood samples being obtained. Clinical, parasitologic and host response (including immunologic) endpoints are being analyzed using appropriate statistical methods, including possible confounders, to determine factors associated with infection and disease in pregnant women and young children. Over the past year, we made a number of key observations: 1) proinflammatory cytokine levels at birth are inversely associated with SMA risk and support the hypothesis that pediatric malarial disease has fetal origins. 2) persistent elevation of HIV replication during and after acute bouts of P. falciparum malaria may be due, at least in part, to ongoing stimulation of CD4(+) T cells by hemozoin-loaded antigen-presenting cells within lymphoid tissues. 3) the pfcrt-SVMNT gene haplotype of drug-resistant P. falciparum parasites, which threatens the efficacy of amodiaquine and was reported in the same time period from Korogwe, Tanzania, 40 Km from Muheza, was not detected in samples from Muheza, tanzania between 2002-2006. Relative low prevalence of pfcrt-SVMNT in Africa may result from genetic or other factors rendering P. falciparum less supportive of this haplotype than in South America or other regions. 4) with our collaborators, we identified several molecules in a small molecule library of 10 000 compounds that could inhibit and reverse binding of IEs to ICAM-1 and CSA receptors, providing new therapeutic candidates for anti-adhesion treatments.